Background/Purpose: The immune landscape of Behçet’s disease (BD) remains ill-defined, lacking a unifying picture, precise disease phenotype-endotype correlations, and an understanding of immunity at target tissue sites. Here, we aim to deconstruct peripheral and target organ-specific immunotypes of BD to define their global and endotype-specific applicability.

Methods: We performed single-cell RNA sequencing and multiparametric flow cytometry on anterior chamber fluid cells and PBMC, subjected plasma to Luminex, and functional immune-phenomics studies on human monocytes and monocyte-derived dendritic cells. We included 26 untreated BD and 22 age and sex-matched HD for single cell and an additional 15 SLE control and 11 HD for functional studies.

Results: We observed global NF-kB activation across all myeloid and T cell subsets with enrichment of conventional dendritic cells (cDC) 2 and cDC1 in the eye and increased numerical representation of activated classical and non-classical monocytes in peripheral blood (PB) in BD. TNFAIP3 (A20) upregulation occurred in BD donors versus HD and all myeloid cell types, NK, and NKT cell subsets, but not in canonical T cells. NF-kB or IFN-mediated monocyte activation was not dependent on soluble factors from BD plasma. Plasmacytoid dendritic cells (pDC) were present in the eye during uveitis, and myeloid cells of uveitic BD patients had a superimposed IFN signature with increased numbers of pDC in PB.

Conclusion: NF-kB-dependent activation globally transcends all myeloid and T cell subsets in BD. Myeloid-centric upregulation of TNFAIP3 transcription points to lineage-dependent counter-regulation of inflammatory activity. We also define a superimposed, IFN-dependent activation profile that includes pDC and subsets of myeloid cells and forms a distinct uveitis endotype within BD, providing rationales for disease-wide and endotype and cell type-specific therapeutic targeting.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/behcets-disease-immune-landscape-exhibits-a-universal-nf-kb-mediated-hyperactivation-pattern-with-cell-specific-tnfaip3-responses-and-a-superimposed-ifn-regulated-endotype/